Insulin is a potent metabolic and growth promoting hormone that acts on cells to stimulate glucose, protein, and lipid metabolism, as well as RNA and DNA synthesis. A well-known effect of insulin is the regulation of glucose levels in the body, which occurs predominantly in liver, fat, and muscle tissue. In the liver, insulin stimulates glucose metabolism into glycogen and inhibits the production of glucose. In muscle and fat tissue, insulin stimulates glucose uptake, storage, and metabolism. Defects in insulin-mediated regulation of blood glucose levels are very common and give rise to disorders such as diabetes and obesity.
Insulin initiates signal transduction in target cells by binding to a specific cell-surface receptor, the insulin receptor (IR). Insulin binding leads to conformational changes in the extracellular domain of the IR, which result in activation of the receptor's tyrosine kinase activity. This, in turn, leads to tyrosine kinase autophosphorylation of the IR, and the recruitment and binding of effector molecules that contain SH2 domains such as phophoinositol-3-kinase (PI3K), Ras GTPase-activating protein, and phospholipase C to the IR. The subsequent phosphorylation and activation of effector molecules (e.g., Ras), leads to phosphorylation of downstream signaling molecules (e.g., ERK, Raf1, MEK, and Akt), and activates immediate/early gene transcription (e.g., c-fos, pip92, egr-1, c-myc, c-jun, jun-B, and fra-1).
Insulin-like growth factor 1 (IGF-1) is a small, single-chain protein that is involved in the regulation of many aspects of tissue growth and repair. Similar to insulin, IGF-1 is thought to have a role in metabolic pathways. IGF-1 also stimulates cell differentiation and cell proliferation and is required by most mammalian cell types for sustained proliferation. IGF-1 has been implicated in various forms of cancer including prostate, breast, colon, ovarian and lung cancers. IGF-1 is similar in size, sequence, and structure to insulin, but has a much lower affinity for the IR. Instead, IGF-1 generally binds to the IGF-1 receptor (IGF-1R).
The insulin/IGF-1 family of receptors consists of three separate receptors that can bind insulin and IGF-1 with varying affinity: insulin receptor (IR), IGF-1 receptor (IGF-1R), and IGF-2 receptor (IGF-2R). A fourth, orphan member of the family is insulin receptor-related receptor (IRR), for which the endogenous ligand is unknown. Three of the four receptors (IR, IGF-1R, and IRR) belong to the family of ligand-activated receptor tyrosine kinases. In contrast, the IGF-2 receptor is a monomeric receptor with a large extracellular domain and no intrinsic signaling capabilities; it serves mainly as a ligand-clearing receptor. The IR and the IGF-1R are expressed at the cell surface as homodimers composed of two identical monomers, or as heterodimers composed of two different receptor monomers (e.g., IGF-1R/IR). These latter receptors are called hybrid receptors and are widely distributed in mammalian tissue and behave in a manner similar to IGF-1R, with respect to ligand-induced autophosphorylation.
Both IGF-1R and IR receptors are composed of two α and two β subunits which form a disulfide-linked heterotetramer (β-α-α-β). These receptors have an extracellular ligand binding domain, a single transmembrane domain, and a cytoplasmic domain displaying the tyrosine kinase activity. The extracellular domain is composed of the entire α subunits and a portion of the N-terminus of the β subunits, while the intracellular portion of the β subunits contains the tyrosine kinase domain.
While similar in structure, IGF-1R and IR serve different physiological functions. IR is primarily involved in metabolic functions whereas IGF-1R mediates growth and differentiation. However, both insulin and IGF-1 can induce mitogenic and metabolic effects via the receptors.
In view of the importance of the signaling pathways mediated by IR and IGF-1R and the role for these receptor proteins in such disorders as diabetes, obesity, neurological conditions, cancer and other cellular proliferative diseases, agonists and antagonists that modulate the signaling activity of each receptor are needed.